Chapter 20 : Inhibitors of the Formation of the First Peptide Bond

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in

Inhibitors of the Formation of the First Peptide Bond, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap20-1.gif /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap20-2.gif


The oxazolidinones are a novel chemical class of synthetic antibacterial agents that target protein synthesis in a wide spectrum of gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococus faecium. In 1987 the antibacterial activities of the oxazolidinones were first described by scientists at E. I. du Pont de Nemours & Co., Inc. It was demonstrated that the oxazolidinone DuP721 inhibited protein synthesis in susceptible bacteria. Oxazolidinones were abandoned for some time after these earlier studies because of their high toxicity. Oxazolidinones are potent inhibitors of bacterial protein biosynthesis. Several hypotheses regarding the mode of inhibition of protein synthesis in sensitive bacteria by oxazolidinone have been proposed. Scientists found that these oxazolidinones inhibit ribosomal peptidyltransferase activity in the simple reaction of 70S ribosomes. Then they proposed that oxazolidinones inhibit bacterial protein biosynthesis by interfering with the binding of initiation fMet-tRNA to the ribosomal peptidyltransferase P site, which is vacant only prior to the formation of the first peptide bond. Then oxazolidinones do not affect the formation of the 30S preinitiation complex but do prevent the formation of the fMet-tRNA–ribosome– mRNA ternary complex. In 2002, Auckland and coworkers reported the first three examples of resistant enterococci (two isolates of E. faecium and one of E. faecalis) isolated in the United Kingdom; they were obtained from patients who had received linezolid.

Citation: Mascaretti O. 2003. Inhibitors of the Formation of the First Peptide Bond, p 279-284. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch20
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 20.1
Figure 20.1

Chemical structures of linezolid, XA043, and DuP721.

Citation: Mascaretti O. 2003. Inhibitors of the Formation of the First Peptide Bond, p 279-284. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 20.2
Figure 20.2

Secondary structure of the segment of E. coli 23S rRNA encompassing the central-loop domain V and the neighboring regions. E. coli linezolid resistance mutations are marked by arrows. Reprinted from L. Xiong, P. Kloss, S. Douthwaite, N. M. Anderson, S. Swaney, D. L. Shinabarger, and A. S. Mankin, J. Bacteriol. 182:5325–5331, 2000, with permission from the American Society for Microbiology.

Citation: Mascaretti O. 2003. Inhibitors of the Formation of the First Peptide Bond, p 279-284. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Brickner, S. J. 1996. Oxazolidinone antibacterial agents. Curr. Pharm. Des. 2:175194.
2. Diekema, D. J.,, and R. N. Jones. 2001. Oxazolidinone antibiotics. Lancet 358:19751982.
3. Diekema, D. J.,, and R. N. Jones. 2000. Oxazolidinones. A review. Drugs 59:716.
4. Ford, C. W.,, J. C. Hamel,, D. Stapert,, J. K. Moerman,, D. K. Hutchinson,, M. R. Barbachyn,, and G. E. Zurenko. 1997. Oxazolidinones, new antibacterial agents. Trends Microbiol. 5:196200.
5. Anonymous. 2000. Linezolid. Med. Lett. 42:4546.
6. Perry, C. M.,, and B. Jarvis. 2001. Linezolid. A review of its use in the management of serious gram-positive infections. Drugs 61:525551.
7. Brown-Elliot, B. A.,, S. C. Ward,, C. J. Crist,, L. B. Mann,, R. W. Wilson,, and R. J. Wallace. 2001. In vitro activities of linezolid against multiple Nocardia species. Antimicrob. Agents Chemother. 45:12951297.
8. Cercenado, E.,, F. Garcia-Garrote,, and E. Bouza. 2001. In vitro activity of linezolid against multiply resistant Gram-positive clinical isolates. J. Antimicrob. Chemother. 47:7781.
9. Eliopoulos, G. M.,, C. B. Wennersten,, H. S. Gold,, and R. C. Moellering. 1996. In vitro activities of new oxazolidinone antimicrobial agents against enterococci. Antimicrob. Agents Chemother. 40:17451747.
10. Patel, R.,, M. S. Rouse,, K. E. Piper,, and J. M. Steckelberg. 2001. Linezolid therapy of vancomycin-resistant Enterococcus faecium experimental endocarditis. Antimicrob. Agents Chemother. 45:621623.
11. Rybak, M. J.,, D. M. Cappelletty,, T. Moldovan,, J. R. Aeschlimann,, and G. W. Kaatz. 1998. Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Antimicrob. Agents Chemother. 42:721724.
12. Wallace, R. J.,, B. A. Brown-Elliott,, S. C. Ward,, C. J. Crist,, L. B. Mann,, and R. W. Wilson. 2001. Activities of linezolid against rapidly growing mycobacteria. Antimicrob. Agents Chemother. 45:764767.
13. Aoki, H.,, L. Ke,, S. M. Poppe,, T. J. Poel,, E. A. Weaver,, R. C. Gadwood,, R. C. Thomas,, D. L. Shinabarger,, and M. C. Ganoza. 2002. Oxazolidinone antibiotics target the P site on Escherichia coli ribosomes. Antimicrob. Agents Chemother. 46:10801085.
14. Kloss, P.,, L. Xiong,, D. L. Shinabarger,, and A. S. Mankin. 1999. Resistance mutations in 23S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center. J. Mol. Biol. 294:93101.
15. Lin, A. H.,, R. W. Murray,, T. J. Vidmar,, and K. R. Marotti. 1997. The oxazolidinone eperezolid binds to the 50S ribosomal subunits and competes with binding of chloramphenicol and lincomycin. Antimicrob. Agents Chemother. 41:21272131.
16. Matassova, N. B.,, M. V. Rodrina,, R. Endermann,, H. P. Knoll,, U. Pleiss,, H. Wild,, and W. Wintermeyer. 1999. Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors. RNA 5:939946.
17. Patel, U.,, Y. P. Yan,, F. W. Hobbs,, J. Kaczmarczyk,, A. M. Slee,, D. L. Pompliano,, M. G. Kurilla,, and E. V. Bobkova. 2001. Oxazolidinones mechanism of action: inhibition of the first peptide bond formation. J. Biol. Chem. 276:3719937205.
18. Shinabarger, D. L.,, K. R. Marotti,, R. W. Murray,, A. H. Lin,, E. P. Melchior,, S. M. Swaney,, D. S. Dunyak,, W. F. Demyan,, and J. M. Buysse. 1997. Mechanism of action of oxazolidinones: effect of linezolid and eperezolid on translation reactions. Antimicrob. Agents Chemother. 41:21322136.
19. Swaney, S. M.,, H. Aoki,, M. C. Ganoza,, and D. L. Shinabarger. 1998. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob. Agents Chemother. 42: 32513255.
20. Zhou, C. C.,, S. M. Swaney,, D. L. Shinabarger,, and B. J. Stockman. 2002. 1H nuclear magnetic resonance study of oxazolidinone binding to bacterial ribosomes. Antimicrob. Agents Chemother. 46:625629.
21. Auckland, C.,, L. Teare,, F. Cooke,, M. E. Kaufmann,, M. Warner,, G. Jones,, K. Bamford,, H. Ayles,, and A. P. Johnson. 2002. Linezolid-resistant enterococci: report of the first isolate in the United Kingdom. J. Antimicrob. Chemother. 50: 743746.
22. Gonzales, R. D.,, P. C. Schreckenberger,, M. B. Graham,, S. Kelkar,, K. DenBesten,, and J. P. Quinn. 2001. Infection due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 357:11791180.
23. Prystowsky, J.,, F. Siddiqui,, J. Cosay,, D. L. Shinabarger,, J. Millichap,, L. R. Peterson,, and G. A. Noskin. 2001. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob. Agents Chemother. 45:21542156.
24. Tsiodras, S.,, H. S. Gold,, G. Sakoulas,, G. M. Eliopoulos,, C. Wennersten,, L. Venkataraman,, R. C. Moellering,, and M. J. Ferraro. 2001. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 358:207208.
25. Xiong, L.,, P. Kloss,, S. Douthwaite,, N. M. Andersen,, S. Swaney,, D. L. Shinabarger,, and A. S. Mankin. 2000. Oxazolidinone resistance mutations in 23S rRNA of Escherichia coli reveal the central region of domain V as the primary site of drug action. J. Bacteriol. 182:53255331.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error